%0 Journal Article
%T Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart against ischemia/reperfusion injury by limiting TNFα-induced mitochondrial injury in experimental diabetes.
%A Baumgardt SL
%A Fang J
%A Fu X
%A Liu Y
%A Xia Z
%A Zhao M
%A Chen L
%A Mishra R
%A Gunasekaran M
%A Saha P
%A Forbess JM
%A Bosnjak ZJ
%A Camara AK
%A Kersten JR
%A Thorp EB
%A Kaushal S
%A Ge ZD
%J Cardiovasc Res
%V 0
%N 0
%D 2024 Jul 13
%M 39001869
%F 13.081
%R 10.1093/cvr/cvae144
%X <B>OBJECTIVE: </B>The histone deacetylase 6 (HDAC6) inhibitor, tubastatin A, reduces myocardial ischemia/reperfusion injury (MIRI) in type 1 diabetic rats. It remains unclear whether HDAC6 regulates MIRI in type 2 diabetic animals. Diabetes augments activity of HDAC6 and generation of tumor necrosis factor α (TNFα) and impairs mitochondrial complex I (mCI). Here we examined how HDAC6 regulates TNFα production, mCI activity, mitochondria, and cardiac function in type 1 and type 2 diabetic mice undergoing MIRI.<BR><B>RESULTS: </B>HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent MIRI in vivo or ex vivo in a Langendorff-perfused system. We found that MIRI and diabetes additively augmented myocardial HDAC6 activity and generation of TNFα, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of ATP. Importantly, genetic disruption of HDAC6 or tubastatin A decreased TNFα levels, mitochondrial fission, and myocardial mitochondrial NADH levels in ischemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or tubastatin A treatment decreased left ventricular dilation and improved cardiac systolic function 28 days after MIRI. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. Hypoxia/reoxygenation augmented HDAC6 activity and TNFα levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown.<BR><B>CONCLUSIONS: </B>HDAC6 is an essential negative regulator of MIRI in diabetes. Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart from MIRI by limiting TNFα-induced mitochondrial injury in experimental diabetes.